Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway by which the brain controls fertility. In the common reproductive disorder polycystic ovary syndrome (PCOS), GnRH neurons are hyperactive, leading to increased frequency of luteinizing hormone (LH) release from the pituitary, driving increased levels of testosterone production. Androgens have a stimulatory role centrally, forming a positive feedback loop to increase GnRH neuron activity. Androgens also interfer with the normal negative feedback actions of progesterone, which typically reduce activity of this system. In addition to infertility, PCOS predisposes women to many metabolic disorders, including insulin resistance, central adiposity and dyslipidemia. Elevated insulin can also act to increase testosterone production, further stimulating the above positive feedback loop. In this proposal, we will examine neurobiological mechanisms underlying the effects of androgens, progesterone and metabolic cues in regulating GnRH neurons, as well as how these factors interact at the central level using state-of-the-art electrophysiological approaches combined with careful animal model development. This main thrust will be complemented by electrophysiological and limited metabolic studies of a mouse model that has many of the phenotypic characteristics of women with PCOS. In Aim 1, the effects of steroids and metabolic cues on the intrinsic properties of GnRH neurons will be studied, including how these factors interact to alter ion channel function. Aim 2 will examine the changes in GABAergic fast synaptic transmission to GnRH neurons that are brought about by steroids and metabolic cues. In Aim 3, we will continue characterization of prenatally androgenized mice as a preclinical model for PCOS. Mice treated prenatally with dihydrotestosterone exhibit disrupted estrous cycles, and elevated levels of testosterone and LH similar to women with PCOS. Preliminary data indicate these mice are glucose intolerant independent of altered adiposity. We will further characterize the metabolic phenotype and examine the causal relationships between reproductive and metabolic aspects of this disorder. Together these studies will provide novel information about the basic biology of GnRH neurons and the pathological state of PCOS that will lead to preclinical and clinical trials of new therapies